The unpredictable heterogeneity in the immunologic setting, development of progressive renal insufficiency and therapeutic response of lupus nephritis is a dominant feature complicating both clinical management and trials. Preliminary data demonstrate the feasibility of studying gene expression profiles by microarray analysis in glomeruli isolated from frozen biopsy sections by laser capture microdissection coupled with an RNA amplification procedure as an approach to gain insight into the molecular mechanisms leading to parenchymal injury. These analyses revealed considerable molecular heterogeneity, with one group of patients characterized by a highly distinct glomerular expression of interferon-alpha-inducible transcripts and a paucity of sclerosis-related transcripts, while others exhibit strong expression of sclerosis-related genes and few interferon-alpha-inducible genes. The goal of the proposed research is to use these technologies to initiate study the heterogeneity in the molecular pathogenesis of lupus nephritis by delineating the transcriptional profile of over and under expressed genes. This technology will be used to search for relevant specific pathogenic processes that could be targets of novel immunomodulatory agents. Aim 1 extends the preliminary findings on the transcriptional phenotype of isolated glomeruli by initiating determining the gene expression pattern in each of the main compartments of the kidney involved by nephritis: glomeruli, tubules, and the periglomerular and intertubular interstitium, to understand better the basis of the heterogeneity in molecular mechanisms of renal injury and interrelationships between glomerular and tubulointerstitial disease. Aim 2 initiates addressing the intriguing, but largely undefined role of intrarenal T cells in lupus using the potential of the technology of single cell laser capture and RNA amplification to investigate several hypotheses concerning the role of T cells in lupus and their potential to act in both afferent and efferent arms of the autoimmune response.